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Introduction

What is the genetic support for the 55 drugs that were approved by the FDA this year (Mullard 2024)? To answer this question requires accessing all current knowledge regarding the association of the drug target to the disease and data analytics capabilities that are provided in platforms like DISGENET (Piñero et al. 2019).

Data

Preprocessing

We will remove from the analysis 4 drugs that target proteins from other organisms (Table 2). Note that two drugs, Defencath and Paxlovid, are combinations targeting both human and non-human organisms and will be included in the analysis using the human target.

Table 2: Drugs without human targets
Drug_brand_name Properties Indication
Lotilaner (Xdemvy) Ectoparasiticide Demodex blepharitis
Nirsevimab (Beyfortus) RSV F protein-targeted mAb RSV lower respiratory tract disease
Rezafungin (Rezzayo) Echinocandin antifungal Candidemia and invasive candidiasis
Sulbactam, durlobactam (Xacduro) β-lactam antibacterial plus a β-lactamase inhibitor Hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible ABC

… and 3 drugs that do not target a gene or protein (Table 3).

Table 3: Drugs without protein/gene targets
Drug_brand_name Properties Indication
Birch triterpenes (Filsuvez) Mechanism unknown Epidermolysis bullosa
Pegunigalsidase alfa (Elfabrio) PEGylated recombinant α-galactosidase Α Fabry disease
Perfluorohexyloctane (Miebo) Semifluorinated alkane Dry eye disease

Converting indications to UMLS identifiers

The remaining 48 drugs are indicated for 46 conditions. We mapped 48 indications to an exact Unified Medical Language System (UMLS) Concept Unique Identifiers (CUI), corresponding to 64 CUIs (Table 4). Using UMLS CUIs allowed more exact mappings of the indications for the drugs, due to the richer and more granular descriptions of phenotypes provided by the UMLS.

Indications with no direct mappings to UMLS were manually assign to similar terms (Table 5).

Table 5: Mappings to similar conditions
Indication diseaseid disease_name
1 AChR- or MuSK-antibody-positive gMG C0751339 Myasthenia Gravis, Generalized
2 AChR-antibody positive gMG C0751339 Myasthenia Gravis, Generalized
3 Anaemia caused by CKD for adults on dialysis C0002871; C1561643 Anemia; Chronic Kidney Diseases
4 Geographic atrophy secondary to AMD C0242383; C1536085 Age related macular degeneration; Geographic Atrophy
5 hATTR with polyneuropathy C0152025 Polyneuropathy
6 Non-CNS manifestations of α-mannosidosis C0024748 alpha-Mannosidosis
7 Proteinuria in primary IgA nephropathy C0033687; C3161650 Proteinuria; Primary immunoglobulin A nephropathy (disorder)
8 RSV lower respiratory tract disease C0035235; C0149725 Respiratory Syncytial Virus Infections; Lower respiratory tract infection
9 SOD1 amyotrophic lateral sclerosis C0002736 Amyotrophic Lateral Sclerosis

Finally, one indication could not be mapped to any concept: (Haematopoietic stem cell mobilization for autologous transplantation in multiple myeloma).

Drug-target information

We used the indications from ChEMBL to find the targets for the FDA approvals (Table 7). All 48 drugs were found to be associated to at least one human target, and the total number of targets is 101

Results

We will use the DISGENET API to retrieve the genes associated to the indications. To perform this operation, you will need to register, to get an API key.

Exact mappings

Using DISGENET information, we find that 33 drugs have at least a gene associated to their indication ( 31) in DISGENET, thus 60 percent of the drugs are supported by genetic info, with exact mappings (counting only the ones that have a human target, thus 55 ).

Figure 1 shows the top scoring gene associated to the pair drug-indication.

Similar mappings

11 drugs where found to have at least a gene associated to their indication ( 11) in DISGENET using the similarity mapping, thus 80 percent of the drugs are supported by genetic info, with exact mappings or similar, out of the total new drugs 55.

Drugs with genetic support for the indication, or a disease similar to the indication

If we consider the drugs that target human proteins, the percent raises to 91.7.

Drug without genetic suppport

Drugs that do not have a genetic support are shown in the table below

Table 10: Drugs without genetic support
Indication Drug_brand_name Symbol
1 Activated PI3Kδ syndrome Leniolisib (Joenja) PIK3CD
2 Haematopoietic stem cell mobilization for autologous transplantation in multiple myeloma Motixafortide (Aphexda) CXCR4
3 Desmoid tumours Nirogacestat (Ogsiveo) APH1A; APH1B; NCSTN; PSEN1; PSEN2; PSENEN
4 CHAPLE disease Pozelimab (Veopoz) C5

Conclusion

In summary, this analysis shows that DISGENET provides genetic support for 91.7% of the drugs approved during 2023 by the FDA. Thus, DISGENET is a key resource for drug R&D to provide actionable information on potential targets for a wide range of indications. In addition, it illustrates the potential of DISGENET as a resource for information on disease biomarkers, as it also contains the evidence that relates the association of the biomarkers with their indications for the two imaging agents approved by the FDA.

References

Mullard, Asher. 2024. “2023 FDA Approvals.” Nature Reviews. Drug Discovery 23 (2): 88–95. https://doi.org/10.1038/d41573-024-00001-x.
Piñero, Janet, Juan Manuel Ramírez-Anguita, Josep Saüch-Pitarch, Francesco Ronzano, Emilio Centeno, Ferran Sanz, and Laura I Furlong. 2019. The DisGeNET knowledge platform for disease genomics: 2019 update.” Nucleic Acids Research, November. https://doi.org/10.1093/nar/gkz1021.